Novel pharmaceutical dosage forms and method for producing same

ABSTRACT

Pharmaceutical dosage forms are produced by injection molding a mixture of an agent and a polymer under pressure, in the presence of a gas or supercritical fluid. Rapid release of the pressure causes the mixture to form a microcellular or supermicrocellular solid. The release of pressure takes place in the mold. The process is especially useful for producing durable flash-dissolve and gastro-retentive tablets.

FIELD OF THE INVENTION

This invention relates generally to pharmaceutical dosage forms andtheir manufacture, and more particularly to a novel dosage form in whichan active agent is combined with a solid excipient having a foamedstructure.

BACKGROUND OF THE INVENTION

Pharmaceutical preparations, especially solid preparations intended fororal administration, are frequently supplied in so-called“flash-dissolve” tablets, which dissolve almost immediately, i.e.,within seconds, upon contact with saliva in the patient's mouth.Flash-dissolve tablets are particularly desirable for use as solidpediatric oral preparations and for administration to adult patients whohave difficulty in swallowing tablets.

Flash-dissolve tablets typically utilize special, highly solubleformulations and disintegration promoters, and also have a high surfacearea-to-volume ratio to promote quick solution. In the past, because oftheir high friability, flash-dissolve tablets could not be subjected topost-formation handling, and to processing steps such as coating,ink-jet printing, etc., without breaking up. Therefore, it has beenconventional practice to produce flash-dissolve tablets by freeze-dryingthe tablet material in the blisters of a blister package in which theywere ultimately to be sold. The tablets took their shape from theblisters, and consequently the shape of the tablets was difficult tocontrol.

In the case of a swallowed tablet, low density is desirable in order tomake the tablet “gastro-retentive”. Unlike a heavier tablet, which wouldpass quickly into the duodenum, a low density tablet can float in thestomach while it dissolves slowly. A low-density, gastro-retentivetablet may be formed, for example, by pressing together grains of porousmaterial formed by extruding a polymer containing a blowing agent and adrug substance, as described in European Patent Application 94924386.9,published on Jun. 26, 1996 under number EP 0 717 988 A1. Anothergastro-retentive tablet is described in U.S. Pat. No. 6,312,726, grantedon Nov. 6, 2001. In accordance with U.S. Pat. No. 6,312,726, anauxiliary blowing agent such as aluminum hydroxide gel, syntheticaluminosilicate, calcium hydrogen phosphate, calcium carbonate, sodiumhydrogen carbonate, calcium hydrogen carbonate or talc, is used as anadditive in order to generate a multiplicity of microfine pores or airspaces uniformly distributed within an extruded pharmaceutical product.The pores are described as having a mean diameter as small as 10-20microns. Conventional low density, gastro-retentive tablets, however,have been prone to-weakness and tend to break apart in handling.Accordingly, they have been subject to problems similar to thoseencountered in the case of flash-dissolve tablets.

Various other porous tablets have been proposed. For example, U.S. Pat.No. 3,885,026, granted on May 20, 1975, describes tablets in which poresare formed by sublimation of an adjuvant such as urethane, urea,ammonium carbonate, etc. in a tablet formed in a tablet press. Thesetablets are porous, but the pores are in the form of comparatively largehollow spaces and canals through which a solvent can penetrate. They arereadily dissolved, but are neither flash-dissolving norgastro-retentive.

U.S. Pat. No. 6,150,424, granted Nov. 21, 2000, describes a process forextruding solid foamed thermoplastic polymer drug carriers with anactive substance produced by melt-extrusion of an active ingredient suchas ibuprofen in the thermoplastic binder, homo- or co-polymers ofN-vinylpyrrolidone along with a blowing agent such as carbon dioxide,nitrogen, air, helium, argon, CFC or N₂O. This process introducesvolatile blowing agents into the extrudate melt. The expanded extrudateis shaped into a dosage form after extrusion.

Another problem encountered in tablet manufacture is that tablets,including porous tablets of the kind described in European PatentApplication 94924386.9, and U.S. Pat. No. 3,885,026, are formed bytablet presses. Such presses, although rapid in their operation, arevery expensive. Furthermore, they must be shut down frequently formaintenance.

Attempts have been made to produce pharmaceutical tablets by injectionmolding, which was a promising alternative to the tablet press method.However, despite these attempts, injection molding has never beensuccessful, and most tablets are still produced by tablet presses.

Various articles of manufacture, such as automobile dashboards, etc.have been formed from resins, such as PET, polystyrene, polyethylene,and PVC, which are expanded by a blowing agent, typically a lowmolecular weight organic compound mixed into a polymer matrix and heatedto cause decomposition of the compound, resulting in the release of agas (or gases) such as nitrogen, carbon dioxide, and carbon monoxide.Resins can also be expanded by physical processes not involvingdecomposition or other chemical reaction. For example, a gas may beintroduced as a component of a polymer charge or introduced underpressure into a molten polymer.

These standard resin expansion processes produce foamed resins havingcells which are relatively large, i.e., on the order of 100 microns, orlarger, with the void fraction, that is the volume of the cells dividedby the total volume, typically ranging from 20%-40% in structural foams,and from 80%-90% in insulation foams. The number of cells produced perunit volume is relatively low (on the order of 106 cells/cm³), and thesize distribution of the cells is typically broad; that is the cell sizeis far from uniform throughout the foamed material.

A great deal of research and development work has been carried out onmicrocellular and supermicrocellular foam process technology. Thistechnology has made it possible to produce expanded plastics having muchsmaller cells, and a much more narrow cell size distribution, with theresult that the plastics exhibit a strength to weight ratiosubstantially greater than that of conventional foamed plastics.Microcellular foaming has proven useful in producing stable, small cell,materials at low cost, and products made from microcellular foams havebeen produced on a commercial scale.

Microcellular plastics are generally defined as foamed plasticscharacterized by cell sizes less than about 100 microns. Typical cellsizes are in the range from about 1 to 100 microns. Cell densities aretypically on the order of 10⁹ cells per cubic centimeter. The specificdensities are typically in the range from 5 to 95 percent of the densityof the polymer, and the void fraction is similarly in the range of about5 to 95 percent. These cells are smaller than the flaws preexistingwithin the polymers and, thus, do not compromise the polymers' specificmechanical properties. The result is a lower density material with nodecrease in specific strength and a significant increase in toughnesscompared to the original polymers.

With a further reduction in cell size and an increase in cell density,supermicrocellular plastics can be produced, having cell sizes less than1 micron, typically in the range from about 0.1 to 1.0 micron.Supermicrocellular plastics can have and cell densities greater than 10⁹cells per cubic centimeter, and may be in the range of 10¹² to 10¹⁵cells per cubic centimeter.

Either microcellular or supermicrocellular plastics may be used in theinvention for producing solid oral dosage forms containing an activeagent. Unless otherwise indicated, the term “microcellular,” as usedherein, should be understood to encompass both microcellular andsupermicrocellular materials.

Microcellular foams, and processes and equipment for makingmicrocellular foams, are described in the following United StatesPatents: 4,473,665 Sep. 25, 1984 Martini-Vvedensky et al. 4,922,082 May1, 1990 Bredt et al. 5,158,986 Oct. 27, 1992 Cha et al. 5,160,674 Nov.3, 1992 Colton et al. 5,334,356 Aug. 2, 1994 Baldwin et al. 5,866,053Feb. 2, 1999 Park et al. 6,005,013 Dec. 21, 1999 Suh et al. 6,051,174Apr. 18, 2000 Park et al. 6,231,942 May 15, 2001 Blizard et al.6,322,347 Nov. 27, 2001 Xu, J.and in published International patent applications WO 98/08667 and WO99/32544. The disclosures of all of the above-listed patents andpublications are here incorporated by reference in their entirety.

In general, microcellular foams are produced by injecting a gas, or asupercritical fluid (SCF), into a polymer while the polymer is underpressure and at an elevated temperature, and then reducing the pressureand temperature to cause a large number of cells to form in the polymer,and controlling the growth of the cells by appropriate processingconditions.

The production of microcellular foams is typically carried out byinjecting a supercritical fluid, for example carbon dioxide, into apolymer while the polymer is maintained under an elevated pressure. Asupercritical fluid is defined as a material maintained at a temperatureexceeding a critical temperature and at a pressure exceeding a criticalpressure so that the material is in a fluid state in which it exhibitsproperties of both a gas and a liquid. The supercritical fluid and thepolymer form a single-phase solution. The pressure acting on thesolution is then rapidly reduced, resulting in controlled nucleation ata very large number of nucleation sites. The gas then forms bubbles, thegrowth of which is controlled by carefully controlling pressure andtemperature. The foams can be injection molded in conventional moldingequipment.

Microcellular foam technology, although highly effective and useful forproducing traditional articles of manufacture, such as automobiledashboards, etc., has not been applied to the pharmaceutical industryfor injection molding of tablets. Apparently, the failures experiencedby pharmaceutical manufacturers in attempts to produce tablets byinjection molding have deterred them from going forward with researchand development in the use of microcellular foam technology.

BRIEF SUMMARY OF THE INVENTION

It has been determined that microcellular foam technology can in fact beutilized successfully in the production of pharmaceutical tablets, andthat microcellular foam technology affords significant advantages, bothin the manufacturing process and in the product itself. Moreparticularly, microcellular foam can produce molded tablets havingdesirable properties and consistent quality, rapidly and at low cost.

In accordance with the invention, pharmaceutically acceptable dosageforms are made by the following steps. First, a non-thermosettingexcipient polymer is supplied. The polymer is preferably pre-mixed witha pharmaceutical agent to form a homogeneous mixture, and heated to forman extrudable mass using a conventional, twin-screw extruder. To formthe pharmaceutical dosage forms, the extruded polymer/pharmaceuticalagent mixture is cut into pellets, which have a free-flowing property.The pellets are fed into the hopper of an injection molding machine, inwhich, while maintaining the polymer at elevated pressure, a singlephase solution is formed, preferably by injecting into the polymer asubstance which is a gas under ambient temperature and pressure, andwhich is substantially non-reactive with the pharmaceutical agent. Thepolymer, which has by this time been mixed homogeneously with thepharmaceutical agent, is then molded into solid dosage forms, and in theprocess of molding the solid dosage forms, the elevated pressure isreduced to a level at which cells are nucleated in large numbers, eachcell containing the gas. After the cells are nucleated, the temperatureof the polymer is rapidly reduced to limit cell growth.

The substance which is introduced into the polymer may be introduced inthe form of a gas. The gas is preferably soluble in the polymer, and,where the gas is soluble, the level to which the elevated pressure isreduced must be a level at which the solution becomes thermodynamicallyunstable and the gas evolves from the solution in the form of bubbles.Alternatively, a gas which is not soluble in the polymer may be used,nitrogen being a typical example. The use of nitrogen is described inU.S. Pat. No. 5,034,171, whose disclosure is incorporated by referencein its entirety herein. In accordance with a preferred method, however,the substance introduced into the polymer is introduced, in the form ofa supercritical fluid.

The pressure and temperature reduction steps are preferably carried outat rates such that the maximum void dimension in the solid dosage formis in the range from about 2 to 100 microns and the void fraction is inthe range of about 5 to 95 percent.

The non-thermosetting polymerized plastics material is preferably apolyol, suitably lactitol, xylitol and sorbitol, erythritol, mannitol,and maltitol. Lactitol is preferred because it is has an ideal meltingpoint, because of its flowability, because it is non-hygroscopic, andbecause it returns to solid form after melting.

Other substances, for example, polyethylene oxide, can be utilized asthe non-thermosetting plastics material. Additional ingredients, such asstarches or compounds classified by their dextrose equivalents, such asmaltodextrin can be included in the polymer.

The process of the invention produces a novel pharmaceutical dosage formin which the active pharmaceutical agent and the solid excipient are incombination as a homogeneous solid mixture primarily in the form of arigid microcellular foam. When the foam is formed into tablets or otherdosage forms by injection molding, the rigid microcellular foam isenclosed within a skin having a density substantially greater than thatof the microcellular foam, but having the same composition as that ofsaid solid mixture.

The homogeneous solid mixture can be made from a composition having asufficiently high solubility in saliva that a tablet composed of themixture will dissolve substantially immediately in the mouth upon oraladministration. Microcellular foam is particularly well suited for usein flash-dissolve tablets. Its cellular structure promotes quicksolution, but it is much less friable than the materials used inconventional flash-dissolve tablets.

The cellular structure of the microcellular foam also enables it to havea low density such that the overall density of the dosage form issubstantially less than that of stomach fluids, so that the dosage formis gastro-retentive.

The technique of saturating a mixture of a polymer and an activepharmaceutical agent with a gas, or introducing a supercritical fluidinto the mixture, can significantly improve the rate of production of anextrudate for injection molding of pharmaceutical dosage forms. Theprocess makes it possible to achieve desired cell sizes and densities ina continuous process, at a reasonable cost, and with superior qualitycontrol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram illustrating the process for producingpharmaceutical dosage forms in accordance with the invention;

FIG. 2 is a schematic view of the extruder and mold;

FIG. 3 is a diagram showing a typical mold cavity configuration; and

FIG. 4 is a photograph illustrating a portion of a pharmaceutical dosageform in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to production of novel drug/activeagent-impregnated microcellular foams, in solid dosage forms such astablets or caplets. By the adaptation of microcellular foam techniques,used heretofore for producing strong, light weight products such asautomotive dashboards and plastic eating utensils, to the manufacture ofpharmaceutical dosage forms, it is now possible to take advantage ofinjection molding or extrusion to produce high quality solid dosageforms that have conventional, time release, or flash-dispersal solutioncharacteristics, and to produce these dosage forms at low cost byforming them continuously over a long time without interruption.

Referring to FIG. 1, as a preliminary step, a pharmaceutically activeagent and a polymer are blended in a powder blender 2 and subjected tomelt extrusion in a conventional twin-screw extruder 4 having a drivemotor 6, a hopper 8 and a pair of screws in side-by-side, meshingrelationship, one of which is seen at 10. Heaters 12, 14 and 16 areprovided along the extruder 4 to establish separate heated zones. Mixingelements 18 are provided at intervals along the screws in order toensure homogeneity in the polymer-pharmaceutical agent blend in theextrusion. A liquid injection port 20 is also provided at a locationabout half way along the length of the barrel of the extruder.

The mixture advanced by the twin screws is extruded through a die 22having a heater 24. The extruded mixture is preferably in the form ofone or more circular cylindrical strands 26, each having a diameter ofabout 2-3mm. The strand 26 is air-cooled on a strand conveyor 28 and cutinto pellets 30, each about 2-3 mm in length, by a strand pelletizer 32comprising a pair of rollers 36 and a rotating cutter 38.

The proportion of active agent in the mixture is typically between 0.1%and 70%, suitably 10-50%, of the total weight of the mixture. Variousadditional ingredients, used to control the properties of the product,or of its intermediate forms, may be included. These additionalingredients may be, for example, binders, sweeteners, flavorants, orcolorants. The additional ingredients may also be disintegrationpromoters such as effervescing agents or substances which absorb waterand expand. Lubricants to prevent the mixture from adhering to the moldmay also be included.

The melt extrusion process results in homogeneous pellets 30, which aredelivered to the injection molding machine 40 as shown in FIG. 2. Thepellets are introduced into a hopper 42, located near one end of anelongated, hollow barrel 44. A heated nozzle 46, formed at the oppositeend of the barrel, is connected to mold 48, which is a multicavity mold.The barrel 44 is heated by an electrical heating coil (not shown) orother suitable heating device in order to melt the pellets after theypass from the hopper into the interior of the barrel. A screw 50 extendslongitudinally within barrel 44, and has a one-way valve 52 at its endnearest the nozzle 46. The screw is rotated by a motor 54, and is alsoreciprocable longitudinally within the barrel by an actuator 56. Thescrew is shown in its withdrawn position. A valve 58 is provided,through which a gas or SCF can be injected into the interior of thebarrel.

In the operation of the injection molding machine, the screw 50 isinitially moved forward to a position in which the one-way valve isseated against seat 60, closing off the nozzle 46 The rotation of thescrew forces the melted mixture forward while causing the screw itselfto move longitudinally in the opposite direction, forming a cushion 62of melted material in the barrel forward of the one-way valve 52. Whilethe screw is operating, gas, or supercritical fluid, is introduced intothe barrel through valve 58. After the cushion is formed, the actuator56 initiates an injection stroke, pushing the screw 50 toward the nozzleand thereby forcing the cushion of melted material through the nozzleand into the mold 48 during the injection stroke.

The mold 48 is a multicavity mold comprising two mating parts, 62 and64, which can be separated from each other for removal of the moldeddosage forms. Each mold part is cooled by passing a coolant through acoolant inlet port 66 and exhausting coolant through a coolant outletport 68. The coolant is cycled through a refrigerator/heat exchanger(not shown). The melted mixture, comprising polymer, activepharmaceutical agent, and dissolved gas or SCF, is injected into mold 48through sprue 70.

In FIG. 3, which illustrates a typical cold runner mold cavityconfiguration, the radial runners 72 connect the centrally located sprue70 to the mold cavities 74, which are disposed in a circular pattern. Inthe configuration shown, each radial runner 72 serves two cavities 74,there being two oblique branches 76 extending respectively to the twocavities from an intermediate point 78 on each radial runner. Theconnection of the oblique runner branches 76 to the radial runners 72 atintermediate points 78, short of the outer ends of the radial runners,ensures that the melted material delivered through each radial runnerwill consistently flow into both cavities served by that runner.

Alternatively, a “hot runner” system, known to those skilled in the art,can be used. In such a system, polymer flowing through the nozzle 46enters heated channels that supply molten polymer to nozzles that feedindividual cavities. Each nozzle is also heated to ensure that thepolymer remains in a molten condition throughout the entire moldingcycle. In this way, material is not wasted, as in the cold runnersystem, and cycle times are reduced, resulting in a more efficientprocess. A “valve-gated” nozzle, one having a central rod for shuttingoff the nozzle outlet, or a “hot-tip” nozzle, where the outlet remainsopen, may be used. The “valve-gated” nozzle is preferred for the moldingof foam tablets, as it will maintain molten material under pressurewhile the mold is opened for the ejection of molded tablets.

The processing of the mixture in injection molding machine 40 ispreferably carried out by injecting a supercritical fluid, such ascarbon dioxide or nitrogen, into the melted mixture within barrel 44 ofthe injection molding machine. At the location at which the fluid isinjected, the pressure on the melted mixture is sufficiently high thatthe fluid remains in its supercritical state, so that the fluid and themelted mixture form a single phase solution. The single phase solutionis then injected, by axial movement of the screw 50, into the mold,where the reduction in pressure allows the supercritical fluid to comeout of solution in the form of gas bubbles. The gas forms a closed cellfoam having a matrix of voids surrounded by a solid lattice. The coolantin the mold limits the expansion of the gas by rapidly solidifying thepolymer, thereby keeping the maximum dimension of the voids within in arange of about 2 to 100 microns, a size much smaller than the voids in aconventionally produced foamed polymer.

As shown in FIG. 4, the voids have a nearly uniform distributionthroughout the foam, and a substantially uniform size, the sizes ofalmost all of the voids being within a relatively small portion of apreferred range of 10 to 50 microns. The void fraction, that is, thevolume of the cells divided by the total volume of the foam, ispreferably in the range of about 5% to 95%.

In accordance with a preferred embodiment of the invention, amicrocellular foamed material is formed by injection molding in threestages. First a polymer/supercritical fluid mixture is formed. Then, theformation of a single-phase polymer/supercritical fluid solution iscompleted. Finally, thermodynamic instability is induced in the solutionto produce nucleation and expansion of the solution to produce a foamedmaterial having a large number of microscopic voids or cells. Althoughthe process specifically described utilizes supercritical fluids,similar techniques can be used to obtain microcellular materials usinggases rather than supercritical fluids.

The polymer/supercritical fluid solution is produced continuously byinjecting a supercritical fluid, such as carbon dioxide or nitrogen,into the molten polymer in the barrel 36 of the injection moldingmachine. The amount of supercritical fluid delivered is preferablymetered either by using a positive displacement pump (not shown), or byvarying the injection pressure of the supercritical fluid as it passesthrough a porous material (not shown), which acts to resist the fluidflow. The metered supercritical fluid is then delivered to the extrusionbarrel where it is mixed with the molten polymer flowing therein to forma single phase polymer/supercritical fluid mixture.

The supercritical fluid in the mixture then diffuses into the polymermelt to complete the formation of a uniform, single-phase solution ofpolymer and supercritical fluid. The weight ratio of supercritical fluidto polymer is typically about 10% or more. The maximum amount of asupercritical fluid soluble in a polymer depends on the working pressureand the temperature of the barrel. Using high pressures and/or lowerprocessing temperatures increases the maximum amount of supercriticalfluid soluble in the polymer. Therefore, higher pressures and/or lowertemperatures are preferable, in order to dissolve the maximum amount ofgas, to achieve a high ratio of supercritical fluid to polymer, and inorder to achieve high nucleation cell densities.

When the polymer/fluid system, containing a sufficient amount ofsupercritical fluid, becomes a uniform and homogeneous single-phasesolution, the pressure is rapidly reduced to induce thermodynamicinstability and to promote a high rate of bubble nucleation in thesolution. Typical pressure drop rates used in accordance with theinvention to produce foamed pharmaceutical dosage forms are higher thanthe rates previously used for producing microcellular foamed parts. Thepressure drop rate in accordance with the invention preferably exceeds0.9 GPa/s.

The nucleated polymer/supercritical fluid solution can be suppliedeither immediately or after a delay, at a selected pressure, to ashaping system such as a die, where expansion and foaming of thesolution occurs. In order to prevent the final cell shape from beingdistorted, the nucleated polymer/supercritical fluid solution can bemaintained under pressure within the die until the shaping process hasbeen completed.

By the technique described above, a continuous stream of microcellular,or supermicrocellular polymer is produced. A wide variety of polymers,including but not limited to amorphous and/or semicrystalline polymers,can be used, so long as they are capable of absorbing a gas or asupercritical fluid. Moreover, any gas or supercritical fluid can beused, provided that it is sufficiently soluble in the polymer that isbeing processed.

Chemical blowing agents may also be used in accordance with theinvention, but must be pharmaceutically acceptable, that is, they mustmeet various guidelines for toxicity, etc. Generally accepted chemicalblowing agents for use in the injection molding of PVC, polypropylene,and polyethylene, for example, include, but are not limited to:azodicarbonamides (NH₂—CON═NCO—NH₂, with or without modifiedsubstitution products), offered by Uniroyal under the trademark CELOGENAZ; sulphonyl hydrazines/dinitropentamethylenetetramine/p-toluenesulphonyl semicarbazide; ammonium or sodium bicarbonate (which uponheating will release CO₂). Both ammonium and sodium bicarbonate are USPreagents and can be ingested. Thus they are preferred chemical blowingagents for use in production of pharmaceutically acceptable tablets.

Suitable gas blowing agents for direct injection into the melted polymerinclude, but are not limited to, chlorofluorocarbons,hydrofluororcarbons, nitrogen, carbon dioxide, argon, and aliphatichydrocarbons.

The chlorofluorocarbons, CFC-11, CFC-12, used historically to makefoamed polystyrene products, but banned in most countries because oftheir ozone depletion potential, have been replaced with HCFCs and HFCs,which exhibit reduced, or zero, ozone depletion potential. DuPontproduces FORMACEL-Z2 (HFC-152a), FORMACEL-S (HCFC-22) and FORMACEL-Z4(HFC-134A) and Elf Atochem produces a similar selection under the brandname FORANE (HFC-141b and HFC-134a). A preferred chlorofluorocarbonblowing agent for use in accordance with the invention is HFC-134a.

Nitrogen, carbon dioxide, and argon, all of which have been injectedinto melts of industrial polymers such as polypropylene, polystyrene andpolyethylene, etc., to form structural foams, are preferred for use inaccordance with the invention, as these gases can be used in thesupercritical range, to produce a finer, more uniform, closed cell size.

Examples of aliphatic hydrocarbons which can be utilized as gas blowingagents for direct injection into the melted polymer, are butane,propane, and heptane.

Reaction injection molding (RIM) is also potentially usable to producemicrocellular products in accordance with the invention. In reactioninjection molding, a polymer mix is heat-activated to initiate achemical reaction in which a gas evolves, forming bubbles in the melt.For example polyurethane foam is generally produced in this manner. Somepolyurethane foams are hydrophilic, can absorb large quantities ofwater, and can be useful as wound dressings. At present polyurethane isnot approved for oral ingestion. However it is contemplated thatsuitable ingestable, microcellular dosage forms can be produced byreaction injection molding.

The process in accordance with the invention can be used to produce awater-soluble foam product which can be formed into a pledgette. Awater-soluble, foam pledgette, suitable for introduction into a nasalpassage, can incorporate a desired active agent or agents, for instancesuitable antibiotics to treat nosocomial infections in patients ormedical staff. The process can also be used to produce water-solublefoam products containing active agents for application to wounddressings. In this case, the active agents can be, for example,mipirocin, the plueromutilins or other topical antibiotics or antiviralagents or co-formulations with other agents, such as silversulfisalizine. Similarly, the water-soluble foam product can be formedinto a suppository or pessary suitable for administration into therectum or vaginal cavity.

The foam product in accordance with the invention can be utilized as apost-surgical sponge to staunch blood flow and absorb secretionsfollowing, for instance, nasal surgery. However unlike conventional,commercially available, post-surgical sponges, which are typically madeof insoluble, but swellable, polyvinyl alcohol (PVA), a post-surgicalsponge in accordance with the invention can utilize a water solublepolymer containing an active agent intended for absorption into thepatient. The post-surgical sponge in accordance with the invention cantherefore have not only a fluid-absorbing effect, but also apharmacological effect.

As mentioned previously, a particularly useful embodiment of thisinvention is a tablet, preferably a flash-dispersion, orflash-dissolving tablet, formed of a microcellular foamed polymer, suchas a polyol or polyethylene oxide, in which an active pharmaceuticalcomposition has been incorporated. Among the advantages of theseflash-dispersion formulations are that they are especially suitable forpediatric patients and others who have difficulty in swallowing, itsease of administration, and the ease with which care givers can confirmdosing in the case of institutionalized patients. The microcellularstructure of the dosage form ensures good control over the void fractionand enables the manufacturer to maintain the dosage in a given tabletwithin very close tolerances. The microcellular internal configurationalso makes it possible to achieve a relatively high void fraction, whichcontributes to rapid solution of the tablet, while at the same timeproducing a tablet having sufficient resistance to breaking up inhandling that it can be supplied in conventional bottles rather than inblister packages.

The tablets can be produced by extrusion without injection molding, inwhich case the dosage can be determined by cutting the extrusion to adesired length. The process of extrusion and cutting has the advantagethat the desired dosage levels can be easily changed. Elimination of theinjection molding step reduces production time, reduces the cost pertablet, and avoids some environmental concerns about coloring andcoating. Preferably, however, the tablet is injection molded, and,unlike the tablet formed by extrusion and cutting, it will have a skinwhich is more dense than the interior of the tablet, as shown in FIG. 4.The skin contributes to the strength of the tablet, and its resistanceto friability, and also makes it possible to print, emboss or engraveinformation on the tablet in the molding process.

In an alternative embodiment, the pharmaceutical composition can beprovided in a non-soluble, acid-stable polymer foam, or an erodablepolymer foam. Because of the foam structure, the density of the tabletcan be made substantially less than the density of stomach fluids. Thelower density dosage form is gastroretentive in that it floats in thestomach fluids, and allows for the leaching of the drug from the foammatrix for gastric delivery, or sustained release gastric delivery.

Various types of final products can be made by the techniques describedherein. These include products in the following general categories:flash dispersal products, buccal dosage products, sachet/effervescentproducts, suppositories or pessaries, and conventional oral tablets.

Flash dispersal products typically provide for delivery of a low dose,high potency drug, preferably containing less than 35 mg of activeagent. Suitable active agents for use herein include REQUIP®, AVANDIA®,PAXIL®, and AMERGE®.

In buccal dosage products, also intended for solution in the mouth, itis preferable that the polymer be sufficiently mucoadhesive to coat thebuccal/sublingual mucosa. Alternatively, if the coating can be retainedin the mouth long enough to allow for drug absorption, and if the drughas a sufficient permeability across mucosa (or an acceptablepermeability enhancer is included), buccal delivery is possible. It ispreferable that the drug has a high water solubility, and high potency(as it is only possible to deliver a few milligrams by buccal delivery).Taste masking may be needed as well. Buccal delivery has onlytraditionally been applied to a handful of products, such asnitroglycerin, the ergot alkaloids, nitrates and selegiline.

Water solubility of the active agent is defined by the United StatesPharmacoepia. Therefore, active agents which meet the criteria of verysoluble, freely soluble, soluble and sparingly soluble as definedtherein are encompassed this invention.

The microcellular foam lends itself especially well to sachet products,which are intended to be dissolved in a glass of water, with or withouteffervescing agents. The foamed structure enhances the solubility of theproduct. The foam may be granulated and packaged as necessary.

In the case of suppositories and pessaries, the final product can beinjection molded to suitable shapes for rectal or vaginal drug delivery.

The process of the invention can, of course, also be used to prepareconventional oral tablets, including immediate release (IR) tablets,sustained release/controlled release (SR/CR) tablets, and even pulsitilerelease (PR) tablets.

The terms “pharmaceutical agent”, “pharmaceutically acceptable agent”,“medicament”, “active agent” and “drug,” are used interchangeablyherein, and include agents having a pharmacological activity in amammal, preferably a human. The pharmacological activity may beprophylactic or for treatment of a disease. The term is not meant toinclude agents intended solely for agricultural and/or insecticidalusage or agents intended solely for application to plants and/or soilfor other purposes.

The term “tablet,” as used herein, is intended to encompass theelongated forms known as “caplets” as well as other similar dosageforms, including coated dosage forms.

The dosage forms in accordance with the invention may also includeadditional pharmaceutically acceptable excipients, including but notlimited to sweeteners, solubility enhancers, binders, colorants,plasticizers, lubricants, (super)disintegrants, opacifiers, fillers,flavorants, and effervescing agents.

Suitable thermoplastic polymers can be preferably selected from knownpharmaceutical excipients. The physico-chemical characteristics of thesepolymers will dictate the design of the dosage form, such as rapiddissolve, immediate release, delayed release, modified release such assustained release, or pulsatile release etc.

However, for purposes herein representative examples of thermoplasticpolymers suitable for pharmaceutical applications, include, but are notlimited to, poly(ethylene oxide), poly(ethylene glycol), especially athigher molecular weights, such as PEG 4000, 6450, 8000, produced by Dowand Union Carbide; polyvinyl alcohol, polyvinyl acetate,polyvinyl-pyrrolidone (PVP, also know as POVIDONE, USP), manufactured byISP-Plasdone or BASF-Kollidon, primarily Grades with lower K values(K-15, K-25, but also K-30 to K-90); copovidone,polyvinylpyrrolidone/vinyl acetate (PVP/VA) (60:40) (also known asCOPOLYVIDONUM, Ph Eur), manufactured by ISP, PLASDONE S-360 or BASFKOLLIDON VA64; hydroxypropylcellulose (HPC), especially at lowermolecular weights, e.g., KLUCEL EF and LF grades, available fromAqualon; polyacrylates and its derivatives such as the Eudragit familyof polymers available from Rohm Pharma, poly(alpha-hydroxy acids) andits copolymers such poly(caprolactone), poly(lactide-co-glycolide),poly(alpha-aminoacids) and its copolymers, poly(orthoesters),polyphosphazenes, poly(phosphoesters), and polyanhydrides, or mixturesthereof.

Most of these pharmaceutically acceptable polymers are described indetail in the Handbook of Pharmaceutical excipients, published jointlyby the American Pharmaceutical association and the Pharmaceuticalsociety of Britain.

Polymeric carriers are divided into three categories: (1)water solublepolymers useful for rapid dissolve and immediate release of activeagents, (2) water insoluble polymers useful for controlled release ofthe active agents; and (3) pH sensitive polymers for pulsatile ortargeted release of active agents. It is recognized that combinations ofboth carriers may be used herein. It is also recognized that several ofthe polyacrylates are pH dependent for the solubility and may fall intoboth categories.

Preferably, a water soluble polymer for use herein ishydroxpropylcellulose or polyethylene oxide, such as the brand namePOLYOX, or mixtures thereof. It is recognized that these polymers may beused in varying molecular weights, with combinations of molecularweights for one polymer being used, such as 100K, 200K, 300K, 400K, 900Kand 2000K. Sentry POLYOX is a water soluble resin which is listed in theNF and have approximate molecular weights from 100K to 900K and 1000K to7000K, and may be used as 1%, 2% and 5% solutions (depending uponmolecular weight).

Additional preferred polymers include povidone, having K values andmolecular weight ranges from: K value Mol. wt. 12    25 15   8000 1710,000 25 30,000 30 50,000 60    400K 90   1000K 120   3000K

These pharmaceutically acceptable polymers and their derivatives arecommercially available and/or be prepared by techniques known in theart. By derivatives it is meant, polymers of varying molecular weight,modification of functional groups of the polymers, or co-polymers ofthese agents, or mixtures thereof.

Another aspect of the present invention is the use of novel,non-thermoplastic or non-thermosetting excipients (i.e., polyols,starches or maltodextrin), which have been found, when combined withother materials or excipients to create a material that behaves as if itwere thermoplastic in the injection molding process. The combination ofmaterials is identified herein as a non-thermosetting polymerizedplastic material (nTPM). For instance, while neither lactitol normaltodextrin are thermoplastic, when blended by hot-melt extrusion, theresultant material can be processed by injection molding as if it were athermoplastic material. Adjusting the amount of water-soluble excipients(i.e., polyols) in the blends will change the disintegration performanceof the material from an immediate release to a more prolongeddisintegration. It should be noted, that be adjusting the amount and/ormolecular weight of a thermoplastic polymeric carriers (i.e.,hydroxypropylcellulose or poly(ethylene oxide)) can effect thedisintegration performance of the material as well. In general, higheramounts and/or high molecular weight polymeric carriers will prolong therelease performance. Adjusting the levels of water-soluble and polymericexcipients can give a wide spectrum of disintegration from immediaterelease too much prolonged (i.e., >24 hours) disintegration of thedosage form.

The non-thermosetting polymerized plastic material is a combination of apolyol, and a non-thermosetting or non-thermoplastic polymer, and/or anon-thermosetting or non-thermoplastic modifier.

For purposes herein representative examples of non-thermoplasticpolymers suitable for pharmaceutical applications, include, but are notlimited to, relatively water soluble polymers such as the cellulosederivatives, such as carboxymethyl cellulose sodium, methyl cellulose,ethylcellulose, hydroxyethylcellulose (HEC), especially at lowermolecular weights, such as NATRASOL 250JR or 250LR, available fromAqualon; hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, noncrystallinecellulose, starch and its derivatives, and sodium starch glycolate. Thethermosetting polymers are typically present in ranges from 2-90%,preferably 5 to 50%. Percentages are in w/w of total dosage form unlessotherwise indicated.

In the invention, the non-thermosetting polymeric excipients can beinherently thermoplastic and therefore be readily injection moldableinto solid dosage forms.

For purposes herein representative examples of non-thermosettingmodifiers suitable for pharmaceutical applications, which in addition toaiding in the production of a non-thermosetting polymerized plasticsmaterial also make a more robust dosage form such as by preventingfriability and holding the product together, and include carrageenan,especially, lambda type, VISCARIN GP-109NF, available from FMC;polyvinyl alcohol, starches; polyalditol, hydrogenated starchhydrosylate, sodium starch glycolate, maltodextrin, dextroseequivalents, dextrin, and gelatin. The thermosetting modifiers aretypically present in ranges from 2-90%, preferably 5 to 50%.

A suitable material which can be processed as non-thermosettingpolymerized plastics material is a polyol, such as lactitol, xylitol,sorbitol, erythritol, maltitol, and mannitol, typically in amountsranging from 5%-70%, preferably 5 to 50%, 5 to 25%. The polyols whichcan also act as sweeteners, may also impart rapid solubility to thedosage form. As noted previously, lactitol as lactitol monohydrate, USP,is a preferred polyol for use in accordance with the invention.

Non-thermosetting modifiers identified as starches, include but are notlimited to pregelatinized Corn Starch, Corn Starch, hydroxyethyl starch,or Waxy maize starch, or mixtures thereof, typically in content rangesfrom 5-25%. Additional reagents, for use herein are the Polyalditols,(e.g. Innovatol PD30 or PD60: the reducing sugars are <1%); andHydrogenated starch hydrosylates (ex. Stabilte SD30 and SD60).

Non-thermosetting modifiers identified as maltodextrins, include but arenot limited to Maltodextrin, typically in a concentration of 5-50%,classified by DE (detrose equivalent) and have a DE range of 5-18. Thelower the DE number the more like starch, which has a DE of about 0. Thehigher the number the more water soluble corn syrup solids, which have aDE range of 20 to 26. Grades that have been found to be useful arecharacterized by Maltrin M150 (DE 13-17), Maltrin M180 (DE 16.5-19.5)and Maltrin QD M550 (DE 13-17) from Grain Processing Corporation.

Suitable colorants for use herein can include food grade soluble dyesand insoluble lakes, and are typically present in ranges of about 0.1 to2%.

Suitable sweeteners can be utilized, in addition to the polyols, such asaspartame, NF, sucralose and saccharin sodium, USP , or mixturesthereof, typically in content ranges from 0.25% to 2%.

Suitable plasticizers, include triacetin, USP, triethyl citrate, FCC,glycerin USP, diethyl phthalate, NF, or tributyl citrate, and mixturesthereof. These liquid plasticizers are typically present in ranges from1 to 10%.

Suitable lubricants, include food grade glycerol monosterate, stearylalcohol NF, stearic acid NF, Cab-O-Sil, Syloid, zinc stearate USP,magnesium stearate NF, calcium stearate NF, sodium stearate,cetostrearyl alcohol NF, sodium stearyl fumerate NF, or talc, USP, andmixtures thereof. The lubricant content is typically in the range from0.1% to 2.5%.

Substances suitable for use as opacifiers/fillers include talc USP,calcium carbonate USP, or kaolin USP, and mixtures thereof. Theopacifier/filler content is typically in the range from 0.5 to 2%.

Suitable effervescing agents, include carbonates and bicarbonates ofsodium, calcium, or ammonium, along with acids such as malic acid andcitric acid, typically in the range from 0.1 to 10%.

Suitable disintegrants and superdisintegrants for use herein include butare not limited to crospovidone, sodium starch glycolate, EudragitL100-55, sodium carboxymethylcellulose, Ac-di-sol®,carboxymethyl-cellulose, microcrystalline cellulose, and croscarmellosesodium alone or in combination, facilitate the disintegration andsolution of the tablet by swelling in the presence of bodily fluids.Disintegrants are typically in the range from 0.1 to 10%.

Suitable binders for use herein include but are not limited to Veegum®,alginates, alginic acid, agar, guar, tragacanth, locust bean, karaya,gelatin, instantly soluble gelatin, carrageenans, and pectin, typicallypresent in an amount of 0.1 to 10%.

It is recognized that certain excipients such as the maltodextrins,starches, hydroxypropylcellulose, hydroxypropylmethyl cellulose, andpolyethylene oxides, will also serve as binders and bulking agents inthe tablets of this invention. These excipients are either soluble orwill absorb water and swell, aiding disintegration of the tablet.

Especially in the production of a flash dispersal tablet, where highwater solubility is desired, excipients from some or all of the abovecategories may be desirable.

For tablets intended to be swallowed, or for controlled or sustainedrelease, excipients from some or all of the above categories may beused, and additional reagents may be desired. The additional reagents,include but are not limited to binders and controlled release (CR)polymers such as, hydroxypropyl-methylcellulose (HMPC),methylcellulose/Na, carboxymethylcellulose, available from Methocels orAqualon, native or modified starches such as corn starch, wheat starch,rice starch, potato starch, tapioca, and amylose/amylopectincombinations in concentrations of 5%-25%. Maltodextrins may also beuseful as a binder or controlled release excipient in concentrations of5%-50.

The injection molding process as used herein requires the active agentto be stable when subjected to heat, but provides for unique tabletshapes, and release profiles not easily attained by conventional tabletpresses.

Suitable pharmaceutically acceptable agents for use in accordance withthe invention can be selected from a variety of known classes of drugsincluding, for example, analgesics, anti-inflammatory agents,anthelmintics, anti-arrhythmic agents, antibiotics (includingpenicillins), anticoagulants, antidepressants, antidiabetic agents,antiepileptics, antihistamines, antihypertensive agents, antimuscarinicagents, antimycobacterial agents, antineoplastic agents,immunosuppressants, antithyroid agents, antiviral agents, anxiolyticsedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptorblocking agents, blood products and substitutes, cardiac inotropicagents, corticosteroids, cough suppressants (expectorants andmucolytics), diagnostic agents, diuretics, dopaminergics(antiparkinsonian agents), haemostatics, immunological agents, lipidregulating agents, muscle relaxants, parasympathomimetics, parathyroid,calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, sexhormones (including steroids), anti-allergic agents, stimulants andanorexics, sympathomimetics, thyroid agents, PDE IV inhibitors,CSBP/RK/p38 inhibitors, vasodilators and xanthines.

Preferred pharmaceutically acceptable agents include those intended fororal administration, or by suitable body cavity administration such asrectal or vaginal administration. A description of these classes ofdrugs and a listing of species within each class can be found inMartindale, The Extra Pharmacopoeia, Twenty-ninth Edition, ThePharmaceutical Press, London, 1989, the disclosure of which is herebyincorporated herein by reference in its entirety. The drug substancescontemplated for use herein are commercially available and/or can beprepared by techniques known in the art.

Suitable active ingredients for incorporation into tablets in accordancewith the invention may include the many bitter or unpleasant tastingdrugs including but not limited to the histamine H2-antagonists, suchas, cimetidine, ranitidine, famotidine, nizatidine, etinidine;lupitidine, nifenidine, niperotidine, roxatidine, sulfotidine,tuvatidine and zaltidine; antibiotics, such as penicillin, ampicillin,amoxycillin, and erythromycin; acetaminophen; aspirin; caffeine,dextromethorphan, diphenhydramine, bromopheniramine, chloropheniramine,theophylline, spironolactone, NSAIDS's such as ibuprofen, ketoprofen,naprosyn, and nabumetone; 5HT4 inhibitors, such as granisetron, orondansetron; seratonin re-uptake inhibitors, such as paroxetine,fluoxetine, and sertraline; vitamins such as ascorbic acid, vitamin A,and vitamin D; dietary minerals and nutrients, such as calciumcarbonate, calcium lactate, etc., or combinations thereof.

Where suitable, the above noted active agents, in particular theanti-inflammatory agents, may also be combined with other activetherapeutic agents, such as various steroids, decongestants,antihistamines, etc.

Examples of numerous suitable excipients include, but are not limited tothe following: Chemical Name Brand Name Supplier Xylitol, NF XylisorbRoquette Hydroxypropyl cellulose, Klucel Aqualon Food Grade Grade EF:Avg MW- 80,000 Grade GF: Avg MW- 370,000 Grade MF: Avg MW- 850,000 GradeHF: Avg MW- 1,150,000 Glycerol Monostearate, Spectrum NF Chem.Croscarmellose Sodium, AcDiSol FMC NF Copovidone, Ph Eur Kollidon VA 64BASF Erythritol, Food Grade C*Eridex 16955 Cerestar Glycerin, USPSpectrum Chem. Sodium Starch Glycolate, Explotab Mendell NF Talc, USPSpectrum Chem. Sorbitol, NF Neosorb Roquette Polyethylene Oxide POLYOXDow Grade WSR-N80, Avg. MW-200,000 Crospovidone, NF Polyplasdone ISPGrade XL-10 Instantly Soluble Gelita Kind & Knox Gelatin Type B,MW-3000-9000 Methacrylic Acid Eudragit L100- Rohm Pharma Copolymer, TypeC, 55 USP/NF Lactitol. Monohydrate, Lacty M Purac USP Alginic AcidSpectrum Chem. Sodium Bicarbonate, USP Baker Citric Acid, MonohydrateSigma Calcium Carbonate, Light Spectrum Powder USP Chem. □-CarrageenanVascarin FMC Type GP-109NF Magnesium aluminum VeeGum F R. T. silicate,Type IB, USP- Vanderbilt NF Polyethylene glycol, NF Polyglycol Dow TypeE4500 Type E8000 Aspartame, NF Spectrum Chem. Spearmint ConcentrateInternational Flavors & Fragrances Maltodextrin Maltrin Grain MaltrinM100, DE 10 Processing Maltrin M150, DE 15 Corp Microcrystaliine Emcocel90 M Mendell cellulose Instantly Soluble Starch PureCote 3793 GrainProcessing Corp Pregelatinized starch NF Starch 1500 ColorconLow-substituted LHPC (LH-11) Shin Etsu hydroxypropyl cellulose

The extrudability of the mixture and its transformation into pellets isimportant to the success of the injection molding process. Accordingly,the extrusion process will now be described by reference to a series ofexamples that are merely illustrative and are not to be construed as alimitation of the scope of the invention. All temperatures are given indegrees Celsius, all solvents are of the highest available purity, andall reactions run under pharmaceutical GMP standards or GLP standardsunless otherwise indicated.

In each example, pellets were formed by extrusion of a polymer. The basepolymer, binder and other major powdered ingredients (polyol, color,filler, sweeteners, and effervescent agents) were blended in a tumbleblender. This blend was then fed into the hopper of a twin-screwextruder where the blend is melted and the screw forces the melt througha 2-3 mm die to make “spaghetti” strands. The strands were air-cooled ona belt conveyer, and then chopped into granules 2-3 mm long by apelletizer, and fed into a drum. If and when liquid plasticizers orcolorants were needed, they were pumped into the polymer meltapproximately half-way along the barrel of the extruder. (Alternatively,metering systems can be implemented to feed individual powders, forinstance, 4-6 powders, into the extruder without need of a tumblemixer.) Various formulations, and their results are given in thefollowing examples. For blends not containing glycerin as a plasticizer,all pre-mixing was done in a tumble blender (not shown). For thoseblends containing glycerin, the glycerin is pumped into the barrel ofthe extruder (through port 20, FIG. 1), using a liquid metering pump(not shown).

In general, for all of the examples, the processing temperatures werebetween 90° C. and 120° C. in the downstream melting zones and die.Extruder speeds, using an APV Baker MP19 extruder with a 25:1 barrel and19 mm, co-rotating twin screws, were in the range of 100-200 rpm.Torque, melt pressure at the die and melt temperatures were recordedduring processing. When appropriate, extrudate was tested for melt flowrate (MFR) using a capillary rheometer (Kayeness LCR Series) with a diediameter of 0.762 mm and die length of 25.4 mm. EXAMPLE 1 Xylitol 25%Hydroxypropyl cellulose, Grade EF 74% Glycerol monostearate  1% Result:extrusion unsuccessful

EXAMPLE 2 Xylitol 25% Hydroxypropyl cellulose, Grade EF 69%Croscarmellose Sodium  5% Glycerol monostearate  1% Result: extrusionsuccessful, but not fast-dissolving

EXAMPLE 3 Xylitol 74% Hydroxypropyl cellulose, Grade EF 20%Croscarmellose Sodium  5% Glycerol monostearate  1% Result: extrusionunsuccessful

EXAMPLE 4 Xylitol 79% Hydroxypropyl cellulose, Grade EF 20% Glycerolmonostearate  1% Result: extrusion unsuccessful

EXAMPLE 5 Xylitol 74% Copovidone 20% Croscarmellose Sodium  5% Glycerolmonostearate  1% Result: extrusion unsuccessful

EXAMPLE 6 Xylitol 79% Crospovidone 20% Glycerol monostearate  1% Result:extrusion unsuccessful

EXAMPLE 7 Erythritol 60% Hydroxypropyl cellulose, Grade EF 38.5%  Glycerol monostearate 2.5%  Result: extrusion unsuccessful Capillaryrheometry: MFR@110° C., 9.537 g/10 min

EXAMPLE 8 Erythritol 60% Copovidone 38.5%   Glycerol monostearate 2.5% Result: extrusion somewhat successful, capillary rheometry: MFR@95° C.,162 g/10 min; Melt viscosity too low to be viable injection moldedmaterial

EXAMPLE 9 Erythritol 60% Hydroxypropyl cellulose, Grade MF 38.5%  Glycerol monostearate 2.5%  Result: extrusion unsuccessful, material tooviscous

EXAMPLE 10 Hydroxypropyl cellulose, Grade EF 92.5% Glycerin   5%Glycerol monostearate  2.5% Result: extrusion successful Capillaryrheometry: MFR@130° C., 21.7 g/10 min

EXAMPLE 11 Hydroxypropyl cellulose, Grade EF 87.5% Glycerin   10%Glycerol monostearate  2.5% Result: extrusion unsuccessful

EXAMPLE 12 Hydroxypropyl cellulose, Grade EF 90.0%  Glycerin 7.5%Glycerol monostearate 2.5% Result: extrusion successful Capillaryrheometry: MFR@130° C., 50.3 g/10 min

EXAMPLE 13 Hydroxypropyl cellulose, Grade EF 91.5%  Glycerin   5%Glycerol monostearate 2.5% Talc 1.0% Result: extrusion successfulCapillary rheometry: MFR@120° C., 8.391 g/10 min

Using the foam tablet process described above, this formulation wasmolded into tablets having up to a 50% weight reduction relative to asolid tablet. EXAMPLE 14 Hydroxypropyl cellulose, Grade EF 53.5% Xylitol40.0% Sodium Starch Glycolate, NF  5.0% Glycerol monostearate  1.5%Result: extrusion unsuccessful, strand too tacky

EXAMPLE 15 Hydroxypropyl cellulose, Grade HF 53.5% Xylitol 40.0% SodiumStarch Glycolate, NF  5.0% Glycerol monostearate  1.5% Result: extrusionunsuccessful, insufficient binder, strand too fragile Capillaryrheometry: viscosity too low for MFR measurement

EXAMPLE 16 Hydroxypropyl cellulose Grade GF 53.5% Xylitol 40.0% SodiumStarch Glycolate, NF  5.0% Glycerol monostearate  1.5% Result: extrusionsomewhat successful Capillary rheometry: MFR@110° C., 107.3 g/10 min

EXAMPLE 17 Hydroxypropyl cellulose, Grade EF 53.5% Sorbitol 40.0% SodiumStarch Glycolate, NF  5.0% Glycerol monostearate  1.5% Result: extrusionsomewhat successful, strand tacky Capillary rheometry: viscosity too lowfor MFR measurement

EXAMPLE 18 Polyethylene oxide (PolyOX, WRS N80) 70% Sorbitol 25% SodiumStarch Glycolate, NF  5% Result: extrusion somewhat successful Capillaryrheometry: MFR too temperature dependent to be useful

EXAMPLE 19 Polyethylene oxide (PolyOX, WRS N80) 45% Sorbitol 50% SodiumStarch Glycolate, NF  5% Result: extrusion somewhat successful Capillaryrheometry: viscosity too high for MFR measurement

EXAMPLE 20 Polyethylene oxide (PolyOX, WRS N80) 38.8%  Sorbitol 49.6% Crospovidone 5.5% Instantly Soluble Gelatin 5.5% Glycerol monostearate1.1% Result: extrusion successful but strand needed to cool on benchCapillary rheometry: MFR@90° C., 7.934 g/10 min MFR@95° C., 163.381 g/10min (MFR too temperature sensitive to be viable)

EXAMPLE 21 Hydroxypropyl cellulose, Grade EF 49%  Sorbitol 40% Crospovidone 5% Instantly Soluble Gelatin 5% Glycerol monostearate 1%Result: extrusion unsuccessful

EXAMPLE 22 Hydroxypropyl cellulose, Grade GF 49%  Sorbitol 40% Crospovidone 5% Instantly Soluble Gelatin 5% Glycerol monostearate 1%Result: extrusion unsuccessful

EXAMPLE 23 Polyethylene oxide (PolyOX, WRS N80) 40%  Sorbitol 49% Crospovidone 5% Eudragit L100-55 5% Glycerol monostearate 1% Result:extrusion poor Capillary rheometry: MFR@90° C., 22.328 g/10 min

EXAMPLE 24 Polyethylene oxide (PolyOX, WRS N80) 40%  Lactitol 49% Crospovidone 5% Eudragit L100-55 5% Glycerol monostearate 1% Result:extrusion acceptable Capillary rheometry: MFR@115° C., 10.870 g/10 min

EXAMPLE 25 Polyethylene oxide (PolyOX, WRS N80) 40%  Lactitol 49% Crospovidone 5% Alginic Acid 5% Glycerol monostearate 1% Result:extrusion acceptable Capillary rheometry: MFR@110° C., 1.726 g/10 min

EXAMPLE 26 Polyethylene oxide (PolyOX, WRS N80) 40%  Lactitol 45% Crospovidone 5% Alginic Acid 5% Sodium bicarbonate 4% Glycerolmonostearate 1% Result: extrusion acceptable Capillary rheometry:MFR@110° C. 1.686 g/10 min

EXAMPLE 27 Polyethylene oxide (PolyOX, WRS N80) 30%  Lactitol 59% Crospovidone 5% Eudragit L100-55 5% Glycerol monostearate 1% Result:extrusion acceptable Capillary rheometry: MFR@110° C., 3.106 g/10 min

EXAMPLE 28 Polyethylene oxide (PolyOX, WRS N80) 20%  Lactitol 69% Crospovidone 5% Eudragit L100-55 5% Glycerol monostearate 1% Result:extrusion unacceptable Capillary rheometry: MFR@110° C., 10.679 g/10 min

EXAMPLE 29 Polyethylene oxide (PolyOX, WRS N80)  30% Lactitol  62%Crospovidone 2.5% Citric Acid 2.5% Calcium bicarbonate 2.5% Glycerolmonostearate 0.5% Result: extrusion unacceptable Capillary rheometry:MFR@105° C., 8.713 g/10 min

EXAMPLE 30 Polyethylene oxide (PolyOX, WRS N80) 40%  Lactitol 49% Crospovidone 5% λ-Carrageenan 5% Glycerol monostearate 1% Result:extrusion acceptable Capillary rheometry: MFR@110° C., 4.143 g/10 min

EXAMPLE 31 Polyethylene oxide (PolyOX, WRS N80) 15% Lactitol 65% CitricAcid  5% Calcium carbonate  5% λ-Carrageenan 10% Result: extrusionunacceptable, insufficient binder Capillary rheometry: MFR@105° C.,2.617 g/10 min

EXAMPLE 32 Polyethylene oxide (PolyOX, WRS N80) 15% Lactitol 55%Sorbitol 10% Citric Acid  5% Calcium carbonate  5% λ-Carrageenan 10%Result: extrusion unacceptable, insufficient binder

EXAMPLE 33 Polyethylene oxide (PolyOX, WRS N80) 25%  Lactitol 60% Citric Acid 5% Calcium carbonate 5% λ-Carrageenan 5% Result: extrusionsomewhat acceptable Capillary rheometry: MFR@105° C., 6.571 g/10 min

EXAMPLE 34 Polyethylene oxide (PolyOX, WRS N80) 25%  Lactitol 60% Citric Acid 5% Sodium bicarbonate 5% λ-Carrageenan 5% Result: extrusionpoor, sodium bicarbonate “volatile”, foaming strand

EXAMPLE 35 Polyethylene oxide (PolyOX, WRS N80) 30% Lactitol 50% CitricAcid  5% Calcium Carbonate 9.5%  VeeGum F  5% Glycerol Monostearate0.5%  Result: extruded well at up to 2 kg/hr Capillary rheometry:MFR@110° C., 0.207 g/10 min, very stiff at this temperature

EXAMPLE 36 Polyethylene oxide (PolyOX, WRS N80) 30% Lactitol 50% CitricAcid  5% Calcium Carbonate 9.5%  Crospovidone  5% Glycerol Monostearate0.5%  Result: extruded well at up to 2 kg/hr Capillary rheometry:MFR@115° C., 0.060 g/10 min, very stiff at this temperature

EXAMPLE 37 Polyethylene oxide (PolyOX, WRS N80) 30% Lactitol 50% CitricAcid  5% Calcium Carbonate 9.5%  Eudragit L100-55  5% GlycerolMonostearate 0.5%  Result: extruded well at up to 2 kg/hr Capillaryrheometry: MFR@110° C., 3.068 g/10 min

EXAMPLE 38 Polyethylene oxide (PolyOX, WRS N80) 25%  Polyethylene glycolE8000 5% Lactitol 50%  Citric Acid 5% Calcium Carbonate 9.5%   EudragitL100-55 5% Glycerol Monostearate 0.5%   Result: extruded well at up to 2kg/hr Capillary rheometry: MFR@110° C., 1.719 g/10 min

EXAMPLE 39 Polyethylene oxide (PolyOX, WRS N80) 24.45%    Polyethyleneglycol E4500 5% Lactitol 50%  Citric Acid 5% Calcium Carbonate 9.5%  Eudragit L100-55 5% Glycerol Monostearate 0.5%   Aspartame 0.5%  Spearmint Concentrate 0.05%   Result: extruded well at 1.5 kg/hrCapillary rheometry: MFR@110 C., 0.685 g/10 min

EXAMPLE 40 Polyethylene oxide (PolyOX, WRS N80) 24.45%    Polyethyleneglycol E4500 5% Lactitol 50%  Citric Acid 5% Calcium Carbonate 9.5%  Eudragit L100-55 5% Glycerol Monostearate 0.5%   Aspartame 0.5%  Spearmint Concentrate 0.05%   Result: extruded well at 1.5 kg/hr 14 kgof this blend were extruded for trial, and the extruded material wasmolded into tablets using the foam tablet process described above.

Capillary rheometry: MFR@105° C., 6.575 g/10 min, MFR@110° C., 7.204g/10 min. Up to a 60% weight reduction relative to a solid tablet wasachieved. EXAMPLE 41 Polyethylene oxide (PolyOX, WRS N80) 19.45% Polyethylene glycol E4500  10% Lactitol  50% Citric Acid   5% CalciumCarbonate 9.5% Eudragit L100-55   5% Glycerol Monostearate 0.5%Aspartame 0.5% Spearmint Concentrate 0.05%  Result: strand broke readilywhen extruded, not a viable formulation

EXAMPLE 42 Lactitol 25% Maltodextrin (Maltrin M100) 70% Sodium StarchGlycolate  5% Result: starch content too high, pressure exceeded maximum

EXAMPLE 43 Lactitol 45% Maltodextrin (Maltrin M100) 50% Sodium StarchGlycolate  5% Result: could be extruded at 2 kg/hr but brittle Capillaryrheometry: MFR@110° C., 41.474 g/10 min

EXAMPLE 44 Lactitol 50% Maltodextrin (Maltrin M150) 45% Sodium StarchGlycolate  5% Result: extruded well at 2 kg/hr Capillary rheometry:MFR@110° C., 37.734 g/10 min

EXAMPLE 45 Lactitol 50% Microcrystalline cellulose (Emcocel 90M) 45%Sodium Starch Glycolate  5% Result: extruded poorly, even at 0.5 kg/hr,too viscous

EXAMPLE 46 Lactitol 50% Maltodextrin (Maltrin M150) 20% Sodium StarchGlycolate 25% Result: extruded poorly, material too thin to pelletize

EXAMPLE 47 Lactitol 50% Mannitol 20% Maltodextrin (Maltrin M150) 20%Instantly Soluble Starch  5% Sodium Starch Glycolate  5% Result:extruded at 2 kg/hr but the strand was very thin, did not pelletizewell, melt viscosity is very low; too low to be injection moldable; noMFR could be calculated.

EXAMPLE 48 Lactitol 50% Mannitol 25% Instantly Soluble Starch 15% SodiumStarch Glycolate 10% Result: extruded at 2 kg/hr but the strand was verythin, did not pelletize well, melt viscosity is very low Capillaryrheometry: MFR@110° C., 119.168 g/10 min

EXAMPLE 49 Lactitol 40% Maltodextrin (Maltrin M150) 50% Sodium StarchGlycolate 10% Result: extruded very well at 2 kg/hour Capillaryrheometry: MFR@110° C., 12.497 g/10 min

EXAMPLE 50 Lactitol 40% Maltodextrin (Maltrin M150) 50% VeeGum F 10%Result: extruded very well at 2 kg/hour Capillary rheometry: MFR@110°C., 13.646 g/10 min

EXAMPLE 51 Lactitol 40% Maltodextrin (Maltrin M150) 50% AcDiSol 10%Result: extruded very well at 2 kg/hour Capillary rheometry: MFR@110°C., 15.312 g/10 min

EXAMPLE 52 Lactitol 40% Maltodextrin (Maltrin M150) 50% Crospovidone 10%Result: extruded very well at 2 kg/hour Capillary rheometry: 8.995 g/10min

EXAMPLE 53 Lactitol 40% Maltodextrin (Maltrin M150) 50% Eudragit L100-5510% Result: extruded very well at 2 kg/hour Capillary rheometry:MFR@110° C., 11.722 g/10 min

EXAMPLE 54 Lactitol 40% Maltodextrin (Maltrin M150) 50% Eudragit L100-55 5% Crospovidone  5% Result: extruded very wall at 2 kg/hour Capillaryrheometry: MFR@115° C., 12.893 g/10 min

EXAMPLE 55 Lactitol 45% Maltodextrin (Maltrin M150) 40% PregelatinizedStarch NF (Starch 1500)  5% Crospovidone 10% Result: extruded very wellat 2 kg/hour Capillary rheometry: MFR@110° C., 6.239 g/10 min

EXAMPLE 56 Lactitol 50% Maltodextrin (Maltrin M150) 30% PregelatinizedStarch NF (Starch 1500) 10% Crospovidone 10% Result: extruded well at 2kg/hour Capillary rheometry: MFR@110° C., 8.075 g/10 min

EXAMPLE 57 Lactitol 45%  Maltodextrin (Maltrin M150) 40%  PregelatinizedStarch NF (Starch 1500) 5% Crospovidone 5% Eudragit L100-55 5% Result:extruded well at 2 kg/hour Capillary rheometry: MFR@110° C., 13.879 g/10min

EXAMPLE 58 Lactitol 65% Pregelatinized Starch NF (Starch 1500) 15%Crospovidone 10% Eudragit L100-55 10% Result: marginal process at 2kg/hour, pelletized poorly with large amount of powder

EXAMPLE 59 Lactitol 60% Crospovidone 20% Eudragit L100-55 20% Result:marginal process at 2 kg/hour, insufficient binder

EXAMPLE 60 Lactitol 40% Calcium carbonate, Light Powder USP 20%Crospovidone 20% Eudragit L100-55 20% Result: marginal process at 1kg/hour, strand very fragile

EXAMPLE 61 Lactitol 50% Erythritol 20% Maltodextrin (Maltrin M150) 25%Sodium Starch Glycolate  5% Result: processing temperature to formstrand very low, ˜70° C., strand required extra cooling time topelletize.

EXAMPLE 62 Lactitol 65% Maltodextrin (Maltrin M150)  5% PregelatinizedStarch NF (Starch 1500) 15% Crospovidone 7.5%  Eudragit L100-55 7.5% Result: extruded at 2 kg/hour, pelletized poorly with large amount ofpowder

EXAMPLE 63 Lactitol 70% Pregelatinized Starch NF (Starch 1500) 15%Crospovidone 7.5%  Eudragit L100-55 7.5%  Result: extruded at 2 kg/hour,pelletized poorly with large amount of powder

EXAMPLE 64 Lactitol 65% Erythritol  5% Pregelatinized Starch NF (Starch1500) 15% Crospovidone 7.5%  Eudragit L100-55 7.5%  Result: extruded at2 kg/hour, pelletized poorly with large amount of powder

EXAMPLE 65 Lactitol 60% Erythritol 10% Pregelatinized Starch NF (Starch1500) 15% Crospovidone 7.5%  Eudragit L100-55 7.5%  Result: extruded at2 kg/hour, but strand thinned and required extra cooling time,pelletized poorly with large amount of powder

EXAMPLE 66 Lactitol 55% Maltodextrin (Maltrin QD550) 40% EudragitL100-55  5% Crospovidone  5% Result: extruded very well at 2 kg/hourCapillary rheometry: MFR@110° C., 18.849 g/10 min

EXAMPLE 67 Lactitol 40% Maltodextrin (Maltrin M180) 50% Eudragit L100-55 5% Crospovidone  5% Result: extruded very well at 2 kg/hour Capillaryrheometry: MFR@110° C., 18.877 g/10 min

EXAMPLE 68 Lactitol 40% Maltodextrin (Maltrin M150) 45% Eudragit L100-557.5%  Crospovidone 7.5%  Result: extruded very well at 2 kg/hourCapillary rheometry: MFR@115° C., 9.103 g/10 min

EXAMPLE 69 Lactitol 40% Maltodextrin (Maltrin M150) 45% Eudragit L100-557.5%  Low-substituted hydroxypropyl cellulose 7.5%  Result: extrudedwell at 1.5 kg/hour but strand was soft Capillary rheometry: MFR@110°C., 13.076 g/10 min

EXAMPLE 70 Lactitol 40% Maltodextrin (Maltrin QD550) 50% EudragitL100-55  5% Crospovidone  5% Result: extruded well at 2 kg/hour butpelletizing was difficult at times Capillary rheometry: MFR@110° C.,14.872 g/10 min

EXAMPLE 71 Lactitol 40%  Maltodextrin (Maltrin QD550) 45.5%   EudragitL100-55 5% Crospovidone 7.5%   Talc, USP 2% Result: extruded very wellat 2 kg/hour Capillary rheometry: MFR@110° C., 14.908 g/10 min

EXAMPLE 72 Lactitol 40% Maltodextrin (Maltrin QD550) 43% EudragitL100-55  5% Crospovidone 10% Talc, USP  2% Result: extruded very well at2 kg/hour Capillary rheometry: MFR@110° C., 8.968 g/10 min

EXAMPLE 73 Lactitol 40%  Maltodextrin (Maltrin QD550) 45.5%   EudragitL100-55 5% Crospovidone 7.5%   Glycerol Monostearate 2% Result: extrudedvery well at 2 kg/hour Capillary rheometry: MFR@110° C., 41.569 g/10 min

EXAMPLE 74 Rosiglitazone maleate (anhydrous) 0.96%   Lactitol 40% Maltodextrin (Maltrin QD550) 44.55%    Eudragit L100-55 5% Crospovidone7.5%   Talc, USP 2% Result: extruded very well at 2 kg/hour Capillaryrheometry: MFR@105° C., 8.868 g/10 min MFR@110° C., 14.251 g/10 minInjection molding of blend attempted using mold in FIG. 3. Solid tabletsejected but runner remained with mold, preventing automatic operation ofthe injection molding machine.

EXAMPLE 75 Hydroxypropyl cellulose, Grade EF 93%  Glycerin 4% Glycerolmonostearate 2% Talc 1% Comment: extrusion successful Capillaryrheometry: MFR@120° C., 6.419 g/10 min Material was successfullyinjection molded into solid forms.

EXAMPLE 76 Carvedilol ® 5.15% Hydroxypropyl cellulose, Grade EF 88.85% Glycerin 4.00% Glycerol monostearate 2.00% Comment: extrusion successfulCapillary rheometry: MFR@120° C., 21.027 g/10 min Material wassuccessfully injection molded into solid forms.

EXAMPLE 77 Carvedilol ® 5.15% Hydroxypropyl cellulose, Grade EF 92.85% Glycerol monostearate 2.00% Comment: extrusion successful. Capillaryrheometry: MFR@120° C., 2.736 g/10 min and @125° C., 5.319 g/10 minMaterial was successfully injection molded into solid forms.

EXAMPLE 78 Carvedilol ® 5.15% Hydroxypropyl cellulose, Grade EF 92.85% Magnesium stearate 2.00% Comment: extrusion successful Capillaryrheometry: MFR@120° C., 6.617 g/10 min Material was successfullyinjection molded into solid forms.

EXAMPLE 79 Carvedilol ® 5.15% Hydroxypropyl cellulose, Grade EF 92.85% Talc 2.00% Comment: extrusion successful Capillary rheometry: MFR@120°C., 8.016 g/10 min Material injection molded poorly.

The inclusion of a polyol (preferably lactitol) in the above examplesserves two purposes. First, it is a water-soluble excipient thatfacilitates disintegration and solution of a flash-dissolve, immediaterelease tablet. Second, at elevated temperatures, it plasticizes theblend, allowing for extrusion and injection molding.

In general, the process temperature was no higher than 120° C.,preferably less than 110° C., and optimally 100° C. or less. The timethe polymer blend is exposed to this elevated temperature is no morethan about two minutes. In this way potential thermal degradation can beminimized.

In general, blends having an MFR between 5 g/10 minutes and 20 g/10minutes at the temperature setting for injection molding (i.e., <120°C.) will have a melt viscosity that will allow the material to beinjection molded.

Glidants, (i.e., talc, USP, and glycerol monostearate) may be needed inthe formulation to prevent tablets from sticking to the mold.

Pellets formed by the melt extrusion process depicted in FIG. 1 were fedinto the hopper of an injection molding machine as depicted in FIG. 2,and melted in the barrel. Using the process described in U.S. Pat. Nos.5,334,356 and 6,051,174, and published International patent applicationsWO 98/08667 and WO 99/32544, supercritical N₂ was injected into themelted polymer in the injection molding machine. The pressure andtemperature were controlled to ensure the supercritical fluid (SCF)formed a single phase with the polymer. The operation of the screw inthe molding machine caused a cushion of melted polymer to form at theinjection end of the barrel. With the mold closed, the polymer wasrapidly forced into the mold by driving the screw forward. Air in themold was forced out during the injection stroke and the mold cavitycompletely filled with polymer. When the pressure was reduced in themold, the gas came out of solution to form microscopic bubbles in thepolymer. The mold was chilled, allowing the polymer to “freeze” intotablet shape. The mold was then opened, and ejection pins popped theresultant tablets out of the mold, depositing them into a drum.

A preferred formulation for about 20 kg of a polymer blend to use inthis process with an active agent is Hydroxypropylcellulose, Grade EF,MW ˜30,000 91.5%  Glycerin (as plasticizer) 5.0% Glycerol monostearate2.5% Talc (nucleating agent for foam) 1.0%

The invention makes it possible to foam tablets, via an injectionmolding process, with an approximately 50% weight reduction relative toa solid tablet, of pharmaceutically acceptable polymers, to package thetablets in bottles or other conventional tablet containers instead ofmolding them in the blister packages in which they are to be sold, andto shape the tablets in any of a broad variety of possible shapes. Oncethe injection molding machine is stabilized, the process may be run withvery little operator involvement, around the clock, producing a veryhomogeneous product.

By utilization of less soluble pharmaceutically acceptable polymers inthe injection molding of tablets, swallowable tablets having varyingrelease characteristics similar to conventional immediate release orcontrolled release tablets may be produced.

The injection molding of tablets (especially flash-release tablets)significantly reduces the complexity of the pharmaceutical manufacturingprocess. The injection molding process of this invention preferablyutilizes a single excipient feed (pellets extruded from a precedingextrusion process producing a homogenous intermediate), and can becarried out using a single fully-automated injection molding pressdesigned for continuous (24 hour, 7 day) operation.

The novel dosage forms of this invention, based upon a water solublefoam, provide for unique drug delivery possibilities.

Various modifications can be made in the formulations and processesdescribed herein. For example, although the preferred process utilizessupercritical N₂ or CO₂ injection, it is possible to produce suitablemicrocellular foamed dosage forms by injection of N₂ or CO₂ in gaseousform under pressure into the polymer melt, or to utilize a chemicalblowing agent or reaction injection molding. Similarly, whereas in thepreferred embodiment, the polymer resin is formulated with the activeagent already incorporated into it, the active agent can be introducedin other ways, for example, it can be injected into the melt in theextruder, or where possible, dissolved in, and injected along with, thesupercritical fluid.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims.

Without further elaboration, it is believed that one skilled in the arecan, using the preceding description, utilize the present invention toits fullest extent. Therefore the Examples herein are to be construed asmerely illustrative and not a limitation of the scope of the inventionin any way. The embodiments of the invention in which an exclusiveproperty or privilege is claimed are defined as follows.

1. A pharmaceutical dosage form suitable for oral administrationcomprising a molded microcellular polymeric material and apharmaceutically acceptable active agent.
 2. The pharmaceutical dosageform according to claim 1 wherein the molded microcellular polymericmaterial is a non-thermosetting polymerized plastics material.
 3. Thepharmaceutical dosage form according to claim 2 wherein thenon-thermosetting polymerized plastics material contains at least onepolyol, and at least one non-thermosetting modifier, and/or anon-thermosetting polymer.
 4. The pharmaceutical dosage form accordingto claim 3 wherein the non-thermosetting polymerized plastics materialcontains at least one polyol, and at least one non-thermosettingmodifier.
 5. The pharmaceutical dosage form according to claim 3 whereinthe polyol is lactitol, xylitol, sorbitol, maltitol, or mannitol, orcombinations thereof.
 6. The pharmaceutical dosage form according toclaim 3 wherein the non-thermosetting modifier is a starch,maltodextrin, a dextrose equivalent, polyalditol a hydrogenated starchhydrosylate, or a mixture thereof.
 7. The pharmaceutical dosage formaccording to claim 6 wherein the starch is pregelatinized corn starch,corn starch, potato starch, rice starch, hydroxyethyl starch, wheatstarch, tapioca starch, or waxy maize starch, or mixtures thereof. 8.The pharmaceutical dosage form according to claim 6 wherein thenon-thermosetting modifier is a maltodextrin.
 9. The pharmaceuticaldosage form according to claim 3 wherein the non-thermosetting polymeris carboxymethyl cellulose sodium, methyl cellulose, ethylcellulose,hydroxyethylcellulose (HEC), hydroxypropylmethyl cellulose (HPMC),hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate,noncrystalline cellulose, starch and its derivatives, and sodium starchglycolate or mixtures thereof.
 10. The pharmaceutical dosage formaccording to claim 1 which optionally further comprises a sweetener, adisintegrant, a binder, a lubricant, or an opacifier.
 11. Thepharmaceutical dosage form according to claim 10 wherein thedisintegrant is croscarmellose sodium, sodium starch glycolate, sodiumcarboxymethyl-cellulose, Ac-di-sol®, carboxymethyl-cellulose, veegum, analginate, agar, guar, tragacanth, locust bean, karaya, pectin, orcrospovidone.
 12. The pharmaceutical dosage form according to claim 10wherein the lubricant is glycerol monosterate, stearyl alcohol NF,stearic acid NF, Cab-O-Sil, Syloid, zinc stearate USP, magnesiumstearate NF, calcium stearate NF, sodium stearate, cetostrearyl alcoholNF, sodium stearyl fumerate NF, or talc.
 13. The pharmaceutical dosageform according to claim 10 wherein the opacifiers is talc USP, calciumcarbonate USP, or kaolin USP.
 14. The pharmaceutical dosage formaccording to claim 1 wherein the pharmaceutically acceptable activeagent is selected from an analgesic, an anti-inflammatory agent, ananthelmintic, anti-arrhythmic, antibiotic, anticoagulant,antidepressant, antidiabetic, antiepileptic, antihistamine,antihypertensive, antimuscarinic, antimycobacterial, antineoplastic,immunosuppressant, antithyroid, antiviral, anxiolytic and sedatives,beta-adrenoceptor blocking agents, cardiac inotropic agent,corticosteroid, cough suppressant, diuretic, dopaminergic, immunologicalagent, lipid regulating agent, muscle relaxant, parasympathomimetic,parathyroid, calcitonin and biphosphonates, prostaglandin,radiopharmaceutical, anti-allergic agent, sympathomimetic, thyroidagent, PDE IV inhibitor, CSBP/RK/p38 inhibitor, and a vasodilator. 15.The pharmaceutical dosage form according to claim 1 wherein the moldedmicrocellular polymeric material is a thermoplastic polymer.
 16. Thepharmaceutical dosage form according to claim 15 wherein thethermoplastic polymer is polyethylene oxide, hydroxypropylcellulose,polyethylene glycol, polyvinyl pyrrolidone, copovidone, or povidone ormixtures thereof.
 17. The pharmaceutical,dosage form according to claim16 wherein the polymer is polyethylene oxide, hydroxypropylcellulose, ora mixture thereof.
 18. The pharmaceutical dosage form according to claim15 which further comprises a non-thermosetting polymerized plasticsmaterial.
 19. The pharmaceutical dosage form according to claim 18wherein the non-thermosetting polymerized plastics material contains atleast one polyol, and at least one non-thermosetting modifier, and/or anon-thermosetting polymer.
 20. The pharmaceutical dosage form accordingclaim 1 wherein the microcellular polymeric material is a closed cellfoam.
 21. A pharmaceutical dosage form comprising: a rigid microcellularfoam consisting of a solid excipient having voids of substantiallyuniform size with a maximum void dimension in the range from about 2 to100 microns and a void fraction in the range of about 5 to 95 percent,the solid excipient comprising a non-thermosetting polymerized plasticmaterial and an active pharmaceutical agent combined in a homogeneoussolid mixture.
 22. The pharmaceutical dosage form according to claim 21wherein the non-thermosetting polymerized plastics material contains atleast one polyol, and at least one non-thermosetting modifier, ornon-thermosetting polymer.
 23. The pharmaceutical dosage form accordingto claim 21 wherein the polyol is lactitol, xylitol, sorbitol, maltitol,or mannitol, or combinations thereof.
 24. The pharmaceutical dosage formaccording to claim 21 wherein the non-thermosetting modifier is astarch, maltodextrin, a dextrose equivalent, polyalditol a hydrogenatedstarch hydrosylate, or a mixture thereof.
 25. The pharmaceutical dosageform according to claim 24 wherein the starch is pregelatinized CornStarch, Corn Starch, Potato starch, Rice starch, hydroxyethyl starch,Wheat starch, Tapioca starch, or Waxy maize starch.
 26. Thepharmaceutical dosage form according to claim 22 wherein thenonthermosetting modifier is a maltodextrin.
 27. The pharmaceuticaldosage form according to claim 21 wherein the non-thermosetting polymeris carboxymethyl cellulose sodium, methyl cellulose, ethylcellulose,hydroxyethylcellulose (HEC), hydroxypropylmethyl cellulose (HPMC),hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate,noncrystalline cellulose, starch and its derivatives, and sodium starchglycolate or mixtures thereof.
 28. The pharmaceutical dosage formaccording claim 1 which optionally further comprises a sweetener, adisintegrant, a binder, a lubricant, or an opacifier.
 29. Thepharmaceutical dosage form according to claim 28 wherein thedisintegrant is croscarmellose sodium, sodium starch glycolate, sodiumcarboxymethyl-cellulose, Ac-di-sol®, carboxymethyl-cellulose, veegum, analginate, agar, guar, tragacanth, locust bean, karaya, pectin, orcrospovidone.
 30. The pharmaceutical dosage form according to claim 28wherein the lubricant is glycerol monosterate, stearyl alcohol NF,stearic acid NF, Cab-O-Sil, Syloid, zinc stearate USP, magnesiumstearate NF, calcium stearate NF, sodium stearate, cetostrearyl alcoholNF, sodium stearyl fumerate NF, or talc.
 31. The pharmaceutical dosageform according to claim 28 wherein the opacifiers is talc USP, calciumcarbonate USP, or kaolin USP.
 32. The pharmaceutical dosage formaccording to claim 21 wherein the active pharmaceutical agent isselected from an analgesic, an anti-inflammatory agent, an anthelmintic,anti-arrhythmic, antibiotic, anticoagulant, antidepressant,antidiabetic, antiepileptic, antihistamine, antihypertensive,antimuscarinic, antimycobacterial, antineoplastic, immunosuppressant,antithyroid, antiviral, anxiolytic and sedatives, beta-adrenoceptorblocking agents, cardiac inotropic agent, corticosteroid, coughsuppressant, diuretic, dopaminergic, immunological agent, lipidregulating agent, muscle relaxant, parasympathomimetic, parathyroid,calcitonin and biphosphonates, prostaglandin, radiopharmaceutical,anti-allergic agent, sympathomimetic, thyroid agent, PDE IV inhibitor,CSBP/RK/p38 inhibitor, and a vasodilator.
 33. The pharmaceutical dosageform according to claim 21 wherein the solid excipient further comprisesa thermoplastic polymer.
 34. The pharmaceutical dosage form according toclaim 33 wherein the thermoplastic polymer is polyethylene oxide,hydroxypropylcellulose, polyethylene glycol, polyvinyl pyrrolidone,copovidone, or povidone or mixtures thereof.
 35. The pharmaceuticaldosage form according to claim 34 wherein the polymer is polyethyleneoxide, hydroxypropylcellulose, or a mixture thereof.
 36. Thepharmaceutical dosage form according to claim 21 wherein thenon-thermosetting polymerized plastics material contains at least onepolyol, and at least one non-thermosetting modifier, and optionally a ora thermosetting polymer.
 37. The pharmaceutical dosage form accordingclaim 21 wherein the microcellular polymeric material is a closed cellfoam.
 38. A pharmaceutical dosage form according to claim 21, in whichthe homogeneous solid mixture has a sufficiently high solubility insaliva that the dosage form dissolves substantially immediately in themouth upon oral administration.
 39. A pharmaceutical dosage formaccording to claim 21, in which the voids are in the form of closedcells.
 40. A pharmaceutical dosage form according to claim 21, in whichthe rigid microcellular foam is enclosed within a skin having a densitysubstantially greater than that of the microcellular foam, but havingthe same composition as that of said solid mixture.
 41. A pharmaceuticaldosage form according to claim 21, in which the overall density of thedosage form is substantially less than that of stomach fluids, wherebythe dosage form is gastro-retentive.
 42. A method for makingpharmaceutically acceptable dosage forms including a pharmaceuticalagent and a non-thermosetting excipient polymer, the method comprisingthe steps of: heating the non-thermosetting excipient polymer to atemperature at which the polymer can be molded; applying pressure to thepolymer to maintain the polymer at elevated pressure; while maintainingthe polymer at elevated pressure, forming a single phase solutioncomprising said polymer and a substance which is substantiallynon-reactive with said pharmaceutical agent to form a single-phasesolution, said substance being a gas under ambient temperature andpressure; forming the polymer into solid dosage forms by injectionmolding; and at a time prior to the forming of the polymer into soliddosage forms, mixing said pharmaceutical agent with the polymer to forma homogeneous mixture; wherein, in the process of forming the polymerinto solid dosage forms, the elevated pressure is reduced to a level atwhich a very large number of cells is nucleated, each cell containingsaid gas; and after the cells are nucleated, the temperature of thepolymer is rapidly reduced to limit cell growth.
 43. The methodaccording to claim 42, in which the step of mixing said pharmaceuticalagent with the polymer to form a homogeneous mixture is carried outprior to the steps of heating and applying pressure.
 44. The methodaccording to claim 42, in which said single phase solution is formed byintroducing said substance into said polymer by injecting said substanceunder pressure.
 45. The method according to claim 42, in which saidsubstance is introduced into the polymer in the form of a gas.
 46. Themethod according to claim 42, in which said substance is introduced intothe polymer in the form of a gas, and the gas introduced into thepolymer remains in solution in the polymer while the polymer is under apressure greater than ambient pressure.
 47. The method according toclaim 42, in which said substance is introduced into the polymer in theform of a gas, the amount of gas introduced into the polymer issufficient to form a saturated single phase solution, and the level towhich the elevated pressure is reduced is a level at which the singlephase solution becomes thermodynamically unstable and gas evolves fromthe solution in the form of bubbles.
 48. The method according to claim42, in which said substance is introduced into the polymer in the formof a supercritical fluid.
 49. The method according to claim 42, in whichthe pressure and temperature reduction steps are carried out at ratessuch that the maximum void dimension in the solid dosage form is in therange from about 2 to 100 microns and the void fraction is in the rangeof about 5 to 95 percent.
 50. The method according to claim 42, in whichthe polymer is formed into pellets by melt extrusion prior to theinjection molding step.